rs11202607

Positions:

• chr10-87967657-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000314.8(PTEN):​c.*2185C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0689 in 219,966 control chromosomes in the GnomAD database, including 589 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.068 (419 hom., cov: 31)
  • Exomes 𝑓: 0.071 (170 hom.)
• Consequence: PTEN NM_000314.8 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.281

Genes affected

PTEN (HGNC:9588): (phosphatase and tensin homolog) This gene was identified as a tumor suppressor that is mutated in a large number of cancers at high frequency. The protein encoded by this gene is a phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase. It contains a tensin like domain as well as a catalytic domain similar to that of the dual specificity protein tyrosine phosphatases. Unlike most of the protein tyrosine phosphatases, this protein preferentially dephosphorylates phosphoinositide substrates. It negatively regulates intracellular levels of phosphatidylinositol-3,4,5-trisphosphate in cells and functions as a tumor suppressor by negatively regulating AKT/PKB signaling pathway. The use of a non-canonical (CUG) upstream initiation site produces a longer isoform that initiates translation with a leucine, and is thought to be preferentially associated with the mitochondrial inner membrane. This longer isoform may help regulate energy metabolism in the mitochondria. A pseudogene of this gene is found on chromosome 9. Alternative splicing and the use of multiple translation start codons results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Feb 2015]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 10-87967657-C-T is Benign according to our data. Variant chr10-87967657-C-T is described in ClinVar as [Benign]. Clinvar id is 301483.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.128 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTEN	NM_000314.8	c.*2185C>T		3_prime_UTR_variant	9/9	ENST00000371953.8
PTEN	NM_001304717.5	c.*2185C>T		3_prime_UTR_variant	10/10
PTEN	NM_001304718.2	c.*2185C>T		3_prime_UTR_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTEN	ENST00000371953.8	c.*2185C>T		3_prime_UTR_variant	9/9	1	NM_000314.8	P1

Frequencies

GnomAD3 genomes AF: 0.0681 AC: 10326 AN: 151706 Hom.: 418 Cov.: 31

Gnomad AFR AF: 0.0430

Gnomad AMI AF: 0.0749

Gnomad AMR AF: 0.133

Gnomad ASJ AF: 0.0594

Gnomad EAS AF: 0.121

Gnomad SAS AF: 0.0464

Gnomad FIN AF: 0.0737

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0657

Gnomad OTH AF: 0.0733

GnomAD4 exome AF: 0.0707 AC: 4820 AN: 68142 Hom.: 170 Cov.: 0 AF XY: 0.0718 AC XY: 2268 AN XY: 31572

Gnomad4 AFR exome AF: 0.0469

Gnomad4 AMR exome AF: 0.151

Gnomad4 ASJ exome AF: 0.0602

Gnomad4 EAS exome AF: 0.0859

Gnomad4 SAS exome AF: 0.0478

Gnomad4 FIN exome AF: 0.0945

Gnomad4 NFE exome AF: 0.0659

Gnomad4 OTH exome AF: 0.0709

GnomAD4 genome AF: 0.0680 AC: 10330 AN: 151824 Hom.: 419 Cov.: 31 AF XY: 0.0687 AC XY: 5097 AN XY: 74218

Gnomad4 AFR AF: 0.0428

Gnomad4 AMR AF: 0.133

Gnomad4 ASJ AF: 0.0594

Gnomad4 EAS AF: 0.121

Gnomad4 SAS AF: 0.0462

Gnomad4 FIN AF: 0.0737

Gnomad4 NFE AF: 0.0657

Gnomad4 OTH AF: 0.0726

Alfa AF: 0.0678 Hom.: 537

Bravo AF: 0.0734

Asia WGS AF: 0.0690 AC: 239 AN: 3468

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

PTEN hamartoma tumor syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.3
DANN	Benign	0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs11202607; hg19: chr10-89727414; COSMIC: COSV64310433;